1-arylsulphonyl-2-pyrrolidinethione or 1-arylsulphonyl-2-piperidinethione derivatives, process for the preparation thereof their application as medicinal products and compositions containing them

ABSTRACT

The invention relates to the products of formula ##STR1## in which R represents the radical ##STR2## in which R 1  at any position on the benzene ring represents a linear, branched or cyclic alkyl, alkenyl or alkynyl containing up to 8 carbon atoms, or the radical ##STR3## in which R 2  and R 3 , which may be identical or different, represent a hydrogen atom or a linear alkyl, alkenyl or alkynyl containing up to 8 carbon atoms or form, together with the nitrogen atom to which they are attached, a carbonaceous heterocyclic radical optionally containing another hetero form, or the radical OR&#39;, R&#39; representing hydrogen, a linear, branched or cyclic alkyl radical containing up to 8 carbon atoms or an aryl radical containing up to 14 carbon atoms, or the radical SR 4  or S(O)R 5 , R 4  and R 5  representing a linear, branched or cyclic alkyl, alkenyl or alkynyl containing up to 8 carbon atoms, or R represents naphthyl optionally substituted with a radical R&#39; 1 , R&#39; 1  having one of the definitions stated above for R 1 , and n represents the number 1 or number 2, to a process for the preparation thereof, to their application as medicinal products and to compositions containing them.

The present invention relates to new 1-arylsulphonyl-2-pyrrolidinethioneor 1-arylsulphonyl-2-piperidinethione derivatives, to a process for thepreparation thereof, to their application as medicinal products and tocompositions containing them.

The subject of the invention is the compounds of formula (I): ##STR4##in which R represents the radical ##STR5## in which R₁ at any positionon the benzene ring represents a linear, branched or cyclic alkyl,alkenyl or alkynyl containing up to 8 carbon atoms, or the radical##STR6## in which R₂ and R₃, which may be identical or different,represent a hydrogen atom or a linear alkyl, alkenyl or alkynylcontaining up to 8 carbon atoms or form, together with the nitrogen atomto which they are attached, a carbonaceous heterocyclic radicaloptionally containing another hetero atom, or the radical OR', R'representing hydrogen, a linear, branched or cyclic alkyl radicalcontaining up to 8 carbon atoms or an aryl radical containing up to 14carbon atoms, or the radical SR₄ or S(O)R₅, R₄ and R₅ representing alinear, branched or cyclic alkyl, alkenyl or alkynyl containing up to 8carbon atoms, or R represents naphthyl optionally substituted with aradical R'₁, R'₁ having one of the definitions stated above for R₁, andn represents the number 1 or number 2.

Alkyl is preferably alkyl containing from 1 to 6 carbon atoms, forexample a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl radical.

Alkenyl is preferably ethenyl, propenyl or butenyl.

Aryl is preferably phenyl or naphthyl.

When R₂ and R₃ form, with the nitrogen atom to which they are attached,a heterocyclic radical optionally containing another hetero atom, theradical in question is preferably piperidyl, piperazinyl, morpholinyl,pyrrolidinyl or hexahydroazepinyl.

Among preferred compounds of the invention, there may be mentioned thecompounds in which R represents the radical ##STR7## R₁ having the samemeaning as above, those in which the radical R₁ is at the 4-position,those in which R₁ represents a linear or branched alkyl containing up to8 carbon atoms, and in particular tert-butyl, those in which R₁represents the radical ##STR8## in which R'₂ and R'₃ represent a linearor branched alkyl containing up to 8 carbon atoms or form, with thenitrogen atom to which they are attached, the heterocyclic radical, oralternatively those in which R₁ represents a radical SR₄, R₄representing a linear or branched alkyl radical containing up to 4carbon atoms, and in particular methyl.

The subject of the invention is more especially the products whosepreparation is given below in the Examples, namely the products ofExamples 1 to 6.

The compounds of formula (I) display advantageous pharmacologicalproperties, and in particular a specific and selective antimuscarinicactivity.

The subject of the invention is hence the products of formula (I) asmedicinal products useful, in particular, for the antispasmodictreatment of muscle spasms in gastroenterology, in gynecology, inobstetrics, in urology, in hepatology and in radiology.

The subject of the invention is more especially, as a medicinal product,the preferred compounds mentioned above, namely the products of Examples1 to 6.

The usual dosage is variable according to the condition in question, thesubject treated and the administration route; it can be between 10 mgand 1 g per day, and preferably between 20 mg and 100 mg per day, forexample between 30 and 60 mg per day in one or more doses for theproduct of Example 1 administered orally.

The subject of the present invention is also pharmaceutical compositionscontaining, as active principle, at least one product of formula (I).The pharmaceutical compositions of the invention can be solid or liquid,and be presented in the pharmaceutical dosage forms commonly used inhuman medicine, such as, for example, simple or sugar-coated tablets,hard gelatin capsules, granules, suppositories or injectablepreparations; they are prepared according to the usual methods.

The active principle or principles may be incorporated therein withexcipients customarily employed in these pharmaceutical compositions,such as talc, gum arabic, lactose, starch, magnesium stearate, cocoabutter, aqueous or non-aqueous vehicles, fats of animal or vegetableorigin, paraffinic derivatives, glycols, various wetting, dispersant oremulsifying agents and preservatives.

The subject of the invention is also a process for preparing compoundsof formula (I), characterized in that a compound of formula (II):##STR9## in which n and R have their meaning above, is subjected to theaction of an agent capable of converting a carbonyl radical to athiocarbonyl radical, to obtain the corresponding compounds of formula(I).

As an agent capable of converting a carbonyl radical to a thiocarbonylradical, there may be mentioned the LAWESSON reagent of formula:##STR10## [See TETRAHEDRON LETTERS 41, 2567 (1985) or TETRAHEDRONLETTERS 41, 5061 (1985).] It is also possible to use other thionatingreagents such as P₂ S₅, P₂ S₅ /piperidine, P₂ S₅ /TEA, P₂ S₅ /NaHCO₃ orPCl₅ /Alk₂ S₃ /Na₂ SO₄.

The products of formula (II) in which n represents the number 1 aredescribed and claimed in the European Patent Application published underNo. 0 033 578 and entitled "Nouveaux derives de la 1-aryl2-pyrrolidinone, leur procede de preparation et les nouveauxintermediaires ainsi obtenus, leur application comme medicaments et lescompositions les renfermant" (New 1-aryl-2-pyrrolidinone derivatives,process for preparation thereof and the new intermediates therebyobtained, their application as medicinal products and compositionscontaining them.)

The compounds of formula (II) in which n represents the number 2 aredescribed and claimed in Italian Patent Application No. 19543-A/89,filed by an associate company of the present assignee and entitled:"Nouveaux derives de la 1-arylsulfonyl 2-piperidone, leur procede depreparation et leur application comme medicaments." (New1-arylsulphonyl-2-piperidone derivatives, process for preparationthereof and their application as medicinal products.)

They may be prepared according to a process which is characterized inthat a compound of formula (II_(A)):

    R--SO.sub.2 --Hal                                          (II.sub.A)

in which Hal represents chlorine or bromine and R retains the meaningstated above, is subjected to the action of 5-aminovaleric acid(III_(A)): ##STR11## to obtain a compound of formula (IV_(A)): ##STR12##which is cyclized to obtain the corresponding product of formula (II) inwhich n represents the number 2.

In a preferred embodiment of the process of the invention:

the condensation of the compound (II_(A)) with 5-amino-valeric acid iscarried out under classical Schotten-Baumann conditions, in the presenceof a base such as sodium hydroxide or potassium hydroxide for example inan organic solvent such as tetrahydrofuran.

The cyclization of the compound of formula (IV_(A)) is carried out bymeans of an acid anhydride such as acetic anhydride, or alternatively bymeans of other condensing agents such as sulphuric acid, phosphoricanhydride, phosphoric acid, metaphosphoric acid,dicyclohexylcarbodiimide in the presence of pyridine orbis(trimethylsilyl)amine with trimethylsilyl chloride.

The compounds of formula (II_(A)) used as starting materials are,generally speaking, known [see Houben Weyl, 4th ed., vol. 9, Ch 18(1955)].

The examples which follow illustrate the invention without, however,limiting the latter.

EXAMPLE 1 1-[4-(Diethylamino)benzenesulphonyl]-2-pyrrolidinethione

A mixture comprising 9 g of1-[4-(diethylamino)benzenesulphonyl]-2-pyrrolidinone, prepared as inExample 2 of the European Patent published under No. 0,033,578, and 6.15g of Lawesson reagent (or2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in180 cm³ of toluene is heated to reflux for 1 hour. The mixture isallowed to return to room temperature and is evaporated to dryness, theresidue is taken up in 200 cm³ of chloroform and the resulting mixtureis dried, filtered on celite and evaporated to dryness. 3.6 g of crudeproduct (m.p. 170°-180° C.) are recovered, which product ischromatographed on silica (eluant: ethyl acetate/n-hexane, 2:1) and theresidue is then crystallized in ethanol. 2.4 g of expected product areobtained. M.p. 183°-184° C.

Analysis: C₁₄ H₂₀ N₂ O₂ S₂ Calculated: C % 53.81, H % 6.45, N % 8.97.Found: C % 54.03, H % 6.38, N % 9.02.

EXAMPLE 2 1-[4-(diethylamino)benzenesulphonyl]-2-piperidinethione

A suspension comprising 5.5 g of1-[4-(diethylamino)benzenesulphonyl]-2-piperidinone and 3.74 g ofLawesson reagent in 80 cm³ of ethylene glycol dimethyl ether is heatedto reflux for 1 hour. The mixture is allowed to return to roomtemperature and is then evaporated to dryness. The residue ischromatographed on silica (eluant: ethyl acetate/n-hexane, 1:1) and 4 gof product (m.p. 135°-140° C.) are obtained, which product is purifiedby 3 successive crystallizations in ethanol. 2 g of expected pureproduct are obtained.

Analysis: C₁₅ H₂₂ N₂ O₂ S₂ Calculated: C % 55.18, H % 6.79, N % 8.58.Found: C % 55.32, H % 6.77, N % 8.73.

1-[4-(diethylamino)benzenesulphonyl]-2-piperidinone used at thebeginning of Example 2 was prepared as follows:

Stage A: 5-(4-Diethylaminobenzenesulphonyl)valeric acid

2.5 g of 4-diethylaminobenzenesulphonyl chloride are added to a solutioncomprising 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxidedissolved in 12 cm³ of water, followed by the addition of 12 cm³ oftetrahydrofuran in order to obtain a solution. The mixture is keptstirring for 2 hours at room temperature, the tetrahydrofuran isevaporated off, the reaction medium is acidified using acetic acid andextracted with chloroform, the organic phase is dried and the solventsare removed under reduced pressure. 2.2 g of expected product areobtained. M.p. 106°-108° C. After crystallization in anisopropanol/water mixture (1:1), the product, melting point 109°-110°C., is obtained.

Analysis: C₁₅ H₂₄ N₂ O₄ S Calculated: C % 54.86, H % 7.36, N % 8.53.Found: C % 54.63, H % 7.28, N % 8.65.

Stage B: 1-[4-(Diethylamino)benzenesulphonyl]-2-piperidinone

2 g of product obtained in Stage A are heated to reflux for 2 hours with2 g of sodium acetate in 20 cm³ of acetic anhydride. The mixture iscooled to room temperature and evaporated to dryness, the residue istaken up in a mixture of chloroform and water, the organic phase isseparated and dried and, after removal of the solvents, 1.8 g ofexpected crude product are obtained. M.p. 118°-120° C. Aftercrystallization in isopropanol, 1.2 g of pure product are obtained. M.p.122°-123° C.

Analysis: C₁₅ H₂₂ N₂ O₃ S Calculated: C % 58.04, H % 7.14, N % 9.02.Found: C % 58.28, H % 7.34, N % 9.09.

4-(Diethylamino)benzenesulphonyl chloride used as a starting materialwas prepared as described in the European Patent Application publishedunder No. 0,033,578.

EXAMPLE 3 1-[4-(1-piperidyl)benzenesulphonyl]-2-pyrrolidinethione

1) A mixture comprising 5 g of1-[4-(1-piperidyl)benzenesulphonyl]-2-pyrrolidinone, prepared as inExample 10 of the European Patent published under No. 0,033,578, and3.28 g of Lawesson reagent (or2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in100 cm³ of dimethoxyethane is heated to reflux for 1 hour. The mixtureis allowed to return to room temperature and is evaporated to dryness,and the residue is chromatographed on silica (eluant: ethylacetate/n-hexane, 1:1). 3.5 g of product are recovered. M.p. 195°-200°C. After crystallization in ethanol, 1.5 g of expected product areobtained. M.p. 211°-212° C.

Analysis: C₁₅ H₂₀ N₂ O₂ S₂ Calculated: C % 55.53, H % 6.21, N % 8.63.Found: C % 55.34, H % 6.23, N % 8.48.

2) A mixture comprising 9.1 g of1-[4-(1-piperidyl)benzenesulphonyl]-2-pyrrolidinone, prepared as inExample 10 of the European Patent published under No. 0,033,578, and5.96 g of Lawesson reagent (or2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in180 cm³ of tetrahydrofuran is heated to reflux for 48 hours. The mixtureis allowed to return to room temperature and is evaporated to dryness,and the residue is chromatographed on silica (eluant: benzene). 4.6 g ofproduct are recovered. M.p. 195°-200° C. After crystallization in achloroform/n-hexane mixture, 4.4 g of expected product are obtained.M.p. 209°-211° C.

Analysis: C₁₅ H₂₀ N₂ O₂ S₂ Calculated: C % 55.53, H % 6.21, N % 8.63.Found: C % 55.21, H % 6.25, N % 8.54.

EXAMPLE 4 1-[4-(1-Piperidyl)benzenesulphonyl]-2-piperidinethione

A suspension comprising 6 g of1-[4-(1-piperidyl)benzenesulphonyl]-2-piperidinone and 3.76 g ofLawesson reagent in 120 cm³ of dimethoxyethane is heated to reflux for 1hour. The mixture is allowed to return to room temperature and is thenevaporated to dryness. The residue is chromatographed on silica (eluant:ethyl acetate/n-hexane, 1:1) and 4 g of product (m.p. 140°-145° C.) areobtained, which product is purified by 3 successive crystallizations inmethanol. 1.5 g of expected pure product are obtained. M.p. 155°-156° C.

Analysis: C₁₆ H₂₂ N₂ O₂ S₂ Calculated: C % 56.77, H % 6.55, N % 8.28.Found: C % 56.54, H % 6.51, N % 8.43.

1-[4-(1-Piperidyl)benzenesulphonyl]-2-piperidinone used at the beginningof Example 4 was prepared as follows:

Stage A: 4-Piperidylbenzenesulphonyl chloride

To a solution, cooled to between 0° C. and -5° C., comprising 8.46 g ofsulphur trioxide in 45 cm³ of methylene chloride, there are addeddropwise 9.3 g of dioxane followed by 17.1 g of N-phenylpiperidinedissolved in 45 cm³ of methylene chloride. The mixture is allowed toreturn to room temperature, then heated to reflux for 1 hour andevaporated to dryness, the residue is neutralized with 10% strengthsodium carbonate solution, the aqueous phase is concentrated and theresidue is dried and treated with 200 cm³ of phosphoryl chloride and21.8 g of phosphorus pentachloride for 12 hours at room temperature. Themixture is evaporated to dryness, the residue is taken up in chloroformwith a little water, the organic phase is separated, dried over sodiumsulphate and filtered and the solvent is evaporated off. 19 g ofexpected product are obtained, which product is used as it is in thenext stage.

Stage B: 5-(4-Piperidylbenzenesulphonylamino)valeric acid

7.8 g of 4-piperidylbenzenesulphonyl chloride are added to a solutioncomprising 3.51 g of 5-aminovaleric acid and 3.6 g of sodium hydroxidedissolved in 35 cm³ of water, followed by the addition of 35 cm³ oftetrahydrofuran in order to obtained a solution. The temperature risesto 35° C. The mixture is kept stirring for 4 hours at room temperature,the tetrahydrofuran is evaporated off, the reaction medium is acidifiedusing acetic acid, diluted with 100 cm³ of water and extracted withchloroform, the organic phase is dried and the solvents are removedunder reduced pressure. 5.8 g of expected product are obtained. M.p.115°-120° C. After crystallization in an isopropanol/water mixture(1:1), the product, melting point 120°-122° C., is obtained.

Analysis: C₁₆ H₂₄ N₂ O₄ S Calculated: C % 56.45, H % 7.10, N % 8.23.Found: C % 56.19, H % 7.05, N % 8.06.

Stage C: 1-[4-(1-piperidyl)benzenesulphonyl]-2-piperidinone

5 g of product obtained in Stage B are heated to reflux for 4 hours with5 g of sodium acetate in 50 cm³ of acetic anhydride. The mixture iscooled to room temperature and evaporated to dryness, the residue istaken up in 50 cm³ of water, filtered off and dried and 4.4 g ofexpected crude product are obtained. M.p. 140°-145° C. Aftercrystallization in ethanol, 3.4 g of pure product are obtained. M.p.145°-146° C.

Analysis: C₁₆ H₂₂ N₂ O₃ S Calculated: C % 59.60, H % 6.88, N % 8.69.Found: C % 59.51, H % 6.97, N % 8.63.

EXAMPLE 51-[4-(1-Hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinethione

1) A mixture comprising 5 g of1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinone, prepared asin Example 18 of the European Patent Application published under No.0,033,578, and 3.13 g of Lawesson reagent (or2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane in 100 cm³ ofdimethoxyethane is heated to reflux for 3 hours. The mixture is allowedto return to room temperature and is evaporated to dryness, and theresidue is chromatographed on silica (eluant: benzene). 2 g of productare recovered. M.p. 168°-170° C. After crystallization in methanol, 1.5g of expected product are obtained. M.p. 172°-173° C.

Analysis: C₁₆ H₂₂ N₂ O₂ S₂ Calculated: C % 56.77, H % 6.55, N % 8.28, S% 18.95. Found: C % 56.85, H % 6.57, N % 8.23, S % 18.86.

2) A mixture comprising 12.53 g of1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinone, prepared asin Example 18 of the European Patent published under No. 0,033,578, and7.5 g of Lawesson reagent (or2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in250 cm³ of tetrahydrofuran is heated to reflux for 48 hours. The mixtureis allowed to return to room temperature and is evaporated to dryness,and the residue is chromatographed on silica (eluant: benzene). 7.3 g ofproduct are recovered. M.p. 173°-175° C. After crystallization in achloroform/n-hexane mixture, 6 g of expected pure product are obtained.M.p. 176°-178° C.

Analysis: C₁₆ H₂₂ N₂ O₂ S₂ Calculated: C % 56.77, H % 6.55, N % 8.28.Found: C % 56.63, H % 6.55, N % 8.20.

EXAMPLE 6 1-[4-(1-Hexahydroazepinyl)benzenesulphonyl]-2-piperidinethione

A solution comprising 5 g of1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-piperidinone and 3 g ofLawesson reagent in 100 cm³ of 1,2-dimethoxyethane is heated to refluxfor 3 hours. The mixture is allowed to return to room temperature and isevaporated to dryness. The residue is chromatographed on silica (eluant:benzene) and 2.5 g of product (m.p. 146°-150° C.) are obtained, whichproduct is crystallized twice in ethanol and then in methanol. 1.5 g ofexpected pure product are obtained. M.p. 152°-153° C.

Analysis: C₁₇ H₂₄ N₂ O₂ S₂ Calculated: C % 57.92, H % 6.86, N % 7.95.Found: C % 57.84, H % 6.87, N % 7.79.

1-[4-(1-Hexahydroazepinyl)benzenesulphonyl]-2-piperidinone used at thebeginning of Example 6 was prepared as follows:

Stage A: 4-(Hexahydroazepinyl)benzenesulphonyl chloride

To a solution, cooled to between +5° C. and +10° C., comprising 2.64 gof sulphur trioxide in 78 cm³ of methylene chloride, there are addeddropwise 2.91 g of dioxane followed by 5.26 g of1-phenylhexahydroazepine (Tetrahedron 41 (1985) p. 101-106) in 53 cm³ ofmethylene chloride. The mixture is allowed to return to roomtemperature, then heated to reflux for 2 hours and cooled again to roomtemperature, 200 cm³ of ethyl ether are added to the suspension, theprecipitate is filtered off, washed with ether and dried and 7.2 g ofacid (m.p. 235° C., decomp.) are obtained, which acid is treated with 36cm³ of phosphoryl chloride in 36 cm³ of methylene chloride and with 5.87g of phosphorus pentachloride for 4 hours at room temperature. Themixture is evaporated to dryness, the residue taken up with 100 cm³ ofwater and 150 cm³ of chloroform, the organic phase is separated, driedover sodium sulphate and filtered and the solvent is evaporated off. 6.6g of expected product are obtained. M.p. 85°-88° C.

Stage B: 5-[4-(1-Hexahydroazepinyl)benzenesulphonylamino]valeric acid

6 g of 4-hexahydroazepinylbenzenesulphonyl chloride are added to asolution comprising 2.56 g of 5-aminovaleric acid and 2.63 g of sodiumhydroxide dissolved in 60 cm³ of water, followed by the addition of 60cm³ of tetrahydrofuran in order to obtain a solution. The mixture iskept stirring for 2 hours at room temperature, the tetrahydrofuran isevaporated off, the reaction medium is acidified using acetic acid, theprecipitate is filtered off, washed with water and dried and 4.65 g ofexpected product are obtained. M.p. 135°-140° C. After crystallizationin isopropanol, the product, melting point 139°-140° C., is obtained.

Analysis: C₁₇ H₂₆ N₂ O₄ S Calculated: C % 57.60, H % 7.39, N % 7.90.Found: C % 57.46, H % 7.37, N % 7.98.

Stage C: 1-[4-(1-Hexahydroazepinyl)benzenesulphonyl]-2-piperidinone

4 g of product obtained in Stage B are heated to reflux for 1 hour with4 g of sodium acetate in 80 cm³ of acetic anhydride. The mixture iscooled to room temperature and evaporated to dryness, the residue istaken up in 60 cm³ of water, filtered and dried and 3.5 g of expectedproduct are obtained. After crystallization in isopropanol, 2.3 g ofproduct are obtained. M.p. 164°- 165° C.

Analysis: C₁₇ H₂₄ N₂ O₃ S Calculated: C % 60.69, H % 7.19, N % 8.33.Found: C % 60.75, H % 7.09, N % 8.41.

Examples of Pharmaceutical Compositions

a) Tablets corresponding to the following formula were prepared:

    ______________________________________                                        Product of Example 1         10 mg                                            Excipient q.s. for a finished tablet weighing                                                             300 mg                                            ______________________________________                                         (Details of the excipient: lactose, wheat starch, treated starch rice         starch, magnesium stearate, talc).                                       

b) Hard gelatin capsules corresponding to the following formula wereprepared:

    ______________________________________                                        Product of Example 1        20 mg                                             Excipient q.s. for a finished hard gelatin                                                               300 mg                                             capsule weighing                                                              ______________________________________                                         (Excipient: talc, magnesium stearate, Aerosil).                          

BIOCHEMICAL AND PHARMACOLOGICAL STUDIES 1) Binding to Different BrainReceptors

a) Muscarinic receptor 1

Preparation of this is carried out from cortices removed from the brainsof male rats weighing 150 to 200 g (Iffa Credo), ground in a Polytron ina 10 mM Na/K buffer pH 7.4. After incubation (0.5 ml aliquots ofhomogenate) for 60 minutes at 25° C. in the presence of 0.25 nM [³H]pirenzepine, either alone, or with the test product, or with an excessof 10⁻⁵ M pirenzepine (to determine the non-specifically boundradioactivity), the incubates are cooled and filtered.

The filtration is performed on Whatman GF/C filters prewashed in a 0.05%strength solution of polyethylenimine. The filters are rinsed with 3×5ml of 10 mM Na/K phosphate buffer pH 7.4 and the measurements are thenperformed by liquid scintillation.

b) Muscarinic receptor 2

The preparation is performed from brains of male rats weighing 150 to200 g (Iffa Credo).

The brains are ground (Teflon-glass) in 0.32M sucrose solution. Thehomogenate is centrifuged for 10 minutes at 1,000 g (0°-4° C.).

The supernatant obtained is collected and centrifuged at 30,000 g for 15minutes (0°-4° C.).

The pellet is resuspended in 50 mM Tris buffer pH 7.5 and the newhomogenate is centrifuged again at 30,000 g for 15 minutes (0°-4° C.).

After removal of the supernatant, the pellets may be used immediately orstored for up to 1 month at -30° C.

For an experiment, the pellets are first thawed, if necessary, at roomtemperature and resuspended using a Dounce in 50 mM Tris buffer pH 7.5.2 ml aliquots are incubated for 60 minutes at 25° C. in the presence of0.3 nM [³ H]quinuclidinyl benzylate, either alone, or with the testproduct, or with 10⁻⁵ M benzatropine to determine the non-specificallybound radioactivity.

At the end of the incubation period, the incubate tubes are cooled to 4°C. and filtered rapidly on Whatman GF/C filters. The filters are rinsedwith 3×5 ml of 50 mM Tris buffer pH 7.5 and the measurements are thenperformed by liquid scintillation (Henry I. Yamamura, Solomon H. Snyder,Proc. Nat. Acad. Sc. (1974) 71, No. 5, 1725-1729).

The results are expressed as an IC₅₀ (concentration needed to inhibit by50% the specifically bound radioactivity).

                  TABLE 1                                                         ______________________________________                                                  Affinity for M.sub.1 and M.sub.2 muscarinic                         Compound of                                                                             receptors                                                           Example   [.sup.3 H]pirenzepine                                                                     [.sup.3 H]quinuclidinyl benzylate                       ______________________________________                                        1         43          2200                                                    2         73          1900                                                    3         25          650                                                     4         30          580                                                     5         10          120                                                     6         12          230                                                     ______________________________________                                    

The compounds of Examples 1 to 6 show a noteworthy advantageous affinityfor the muscarinic receptor, and mainly for the M₁ type receptor. Incontrast, the same compounds showed negligible affinity(IC₅₀ >5,000-10,000) for the other receptors examined, including thosefor dopamine, histamine, serotonin (5-HT₁ and 5-HT₂), benzodiazepines,GABA, adrenoreceptors (alpha₁, alpha₂, beta₁, beta₂) or alternativelyopiate receptors (mu, kappa).

2) Interaction and Affinity With Different Intestinal Receptors

The interaction of the compounds with different receptors was assessedon isolated guinea pig ileum according to the following method.

Guinea pig ileum segments measuring 2.5-3 cm were washed and immediatelysuspended in a bath containing 10 ml of Tyrode's solution at 37° C.aerated with a mixture of oxygen (95%) and carbon dioxide (5%). After astabilization period of at least 30 minutes, the contractions wererecorded, maintaining the preparation under constant tension of 1 gusing a gauge connected to a polygraph. The agonist action was assessedby leaving the compound in contact with the isolated tissue for a periodnecessary for expressing the maximal contraction; the preparation wasthen washed with Tyrode's solution. The next dose was added to the bathonly after the preparation had returned to its base line. As a referenceproduct, arecoline was employed. The antagonist action was assessed oncontractions induced by acetylchloine (1×10⁻⁶ M), histamine (1×10⁻⁵ M)and barium chloride (2×10⁻⁴ M). Atropine, diphenhydramine and papaverinewere employed as reference products. The contact time before adding theagonist was one minute.

For each compound, the dose-response curves are obtained with 4 to 6different concentrations and 3 to 5 independent tests. The agonistactivity is expressed by pD₂ (negative logarithm of the dose whichproduces 50% of the maximum effect). The antagonist activity isexpressed by IC₅₀ (concentration inhibiting 50% of the maximalresponse).

The results obtained with the compounds of Examples 1 to 6 are recordedin the following table:

                  TABLE 2                                                         ______________________________________                                                  Antagonist to different                                                       agents                Agonist                                       Compound of                                                                             (IC.sub.50 :M)        action                                        Example   ACh       Histam.   BaCl.sub.2                                                                            pD.sub.2                                ______________________________________                                        1         5.7 × 10.sup.-7                                                                   >10.sup.-5                                                                              >10.sup.-5                                                                            <5                                      2         3.4 × 10.sup.-7                                                                   >10.sup.-5                                                                              >10.sup.-5                                                                            <5                                      3         2.6 × 10.sup.-6                                                                             >10.sup.-5                                                                            <5                                      4         3.6 × 10.sup.-6                                                                             >10.sup.-5                                                                            <5                                      5         2.8 × 10.sup.-7                                                                             >10.sup.-5                                                                            <5                                      6         1.9 × 10.sup.-7                                                                             >10.sup.-5                                                                            <5                                      Atropine  9.5 × 10.sup.-9                                               Diphenhydra-        8.3 × 10.sup.-7                                     mine                                                                          Papaverine                    4.5 × 10.sup.-5                           Arecoline                             6.68                                    ______________________________________                                    

The "in vitro" studies on isolated guinea pig ileum demonstrated thatthe compounds of the invention are antimuscarinic agents. Theyantagonize contractions induced by acetylcholine, but not those inducedby histamine and barium chloride.

3) "In Vivo" Anticholinergic Action

The anticholinergic activity of the compounds was determined byassessing the capacity to inhibit the cholinomimetic effects induced bycarbachol. Atropine sulphate was employed as a reference product.

CD₁ male mice weighing 25 to 30 g were used. They were distributed ingroups of 6 animals and treated intraperitoneally with scalar doses ofthe products or 0.25% Methocel for the controls. 12 animals were usedfor each dose. 30 minutes after administration of the compounds, themice were injected subcutaneously with 1 mg/kg of carbachol dissolved inphysiological saline.

Each animal was examined 30 minutes after the injection of carbachol toassess the presence of diarrhoea, salivation and eye watering; inaddition, the body temperature was measured by means of a thermocoupleinserted 1.5 cm into the rectum.

Carbachol (1 mg/kg s.c.) induced diarrhoea, salivation and eye wateringin all the control mice, and a decrease in rectal temperature ofapproximately 2.5° C.

For each compound, we have determined and recorded in the followingtable the dose capable of inhibiting the appearance of thecarbachol-induced cholinometric symptoms in 50% of the animals, and ofincreasing by 1° C. the hypothermic effect induced by the cholinergicagent.

                  TABLE 3                                                         ______________________________________                                        Compound                                                                              Dose mg/kg i.p.                                                       of      Diar-     Sali-     Eye     Body                                      Example rhoea     vation    watering                                                                              temperature                               ______________________________________                                        1       5         >50       >50     >50                                       2       8         >50       >50     >50                                       3       3         >50       >50     >50                                       4       7         >50       >50     >50                                       5         0.6      15       >50      12                                       6       2          40       >50     >50                                       Atropine                                                                                0.04        0.06      0.05                                                                                  0.03                                  ______________________________________                                    

The results obtained show that, in contrast to atropine, the compoundsexert "in vivo" a selective anticholinergic action in respect of theintestinal musculature.

What is claimed is:
 1. The compounds of formula (I): ##STR13## in whichR represents the radical ##STR14## in which R₁ at any position on thebenzene ring represents linear, branched or cyclic alkyl containing upto 8 carbon atoms, alkenyl containing up to 8 carbon atoms or alkynylcontaining up to 8 carbon atoms, or the radical ##STR15## in which R²and R₃, which may be identical or different, represent hydrogen orlinear alkyl containing up to 8 carbon atoms, alkenyl containing up to 8carbon atoms or alkynyl containing up to 8 carbon atoms or form,together with the nitrogen atom to which they are attached, piperidyl,piperazinyl, morpholinyl, pyrrolidinyl or hexahydroazepinyl, or theradical OR', R' representing hydrogen, linear, branched or cyclic alkylcontaining up to 8 carbon atoms, phenyl or naphthyl, or the radical SR₄or S(O)R₅, R₄ and R₅ representing linear, branched or cyclic alkylcontaining up to 8 carbon atoms, alkenyl containing up to 8 carbon atomsor alkynyl containing up to 8 carbon atoms, or R represents naphthyloptionally substituted with a radical R'₁, R'₁ having one of thedefinitions stated above for R₁, and n represents the number 1 or number2.
 2. The compounds of formula (I) as defined in claim 1, in which Rrepresents the radical ##STR16## R₁ retaining the same meaning as inclaim
 1. 3. The compounds of formula (I) as defined in claim 2, in whichR₁ is at the 4-position.
 4. The compounds of formula (I) as defined inclaim 2 or 3, in which R₁ represents a linear or branched alkylcontaining up to 8 carbon atoms.
 5. The compounds of formula (I) asdefined in claim 2 or 3, in which R₁ represents the radical ##STR17## inwhich R'₂ and R'₃ represent linear or branched alkyl containing up to 8carbon atoms or form, together with the nitrogen atom to which they areattached, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl orhexahydroazepinyl.
 6. The compounds of formula (I) as defined in claim 2or 3, in which R₁ represents the radical SR₄, R₄ representing a linearor branched alkyl containing up to 4 carbon atoms.
 7. The compound offormula (I), as defined in claim 1, selected from the group consistingof1-[4-(diethylamino)phenylsulphonyl]-2-pyrrolidinethione,1-[4-(diethylamino)phenylsulphonyl]-2-piporidinethione,1-[4-(1-piperidyl)phenylsulphonyl]-2-pyrrolidinethione,1-[4-(1-piperidyl)phenylsulphonyl]-2-piperidinethione,1-[4-(1-hexahydroazepinyl)phenylsulphonyl]-2-pyrrolidinethione, and1-[4-(1-hexahydroazepinyl)phenylsulphonyl]-2-piperidinethione.
 8. Atherapeutic composition for the treatment of a patient suffering frommuscle spasms, comprising an anti-spasmodically effective amount of acompound as defined in claim 1 and a pharmacologically acceptablecarrier.
 9. A therapeutic composition for the treatment of a patientsuffering from muscle spasms, comprising an anti-spasmodically effectiveamount of a compound as defined in claim 7 and a pharmacologicallyacceptable carrier.
 10. A method of treating a patient suffering frommuscle spasms comprising administering to the patient ananti-spasmodically effective amount of a compound as defined in claim 1.11. A method of treating a patient suffering from muscle spasmscomprising administering to the patient an anti-spasmodically effectiveamount of a compound as defined in claim 7.